MAPPING AND CHARACTERIZATION OF NON-HLA MULTIGENE ASSEMBLAGES IN THE HUMAN MHC CLASS-I REGION

The major histocompatibility complex (MHC) class I region has been sho wn to be associated with a variety of immune and nonimmune disorders. In an effort to initiate steps designed to identify the idiopathic hem ochromatosis disease gene (HFE), we have cloned and mapped two express ed messages using probes from the HLA-H subregion that lie immediately distal to the HLA-AS breakpoint. Although the cDNA clones identify di stinct multifragment families that are dispersed throughout the MHC, t he gene sequences from which the two cDNA clones derive map centromeri c to the HLA-B locus and are absent from the genomes of higher nonhuma n primates. This suggests that a syntenic coding segment arose within a highly polymorphic region (TNF to HLA-B interval) as the result of a n insertion event following the emergence of Home sapiens. An addition al syntenic cluster exists within a peak of linkage disequilibrium wit h the HFE gene and may define coding sequences that underlie the defec t in genetic iron overload. These data generally support the concept t hat the class I region is potentially gene-rich and further highlight the possibility that these new coding sequences may play a role in the development of a variety of HLA-linked diseases. The observations pre sented suggest that interlocus exchanges have played a structural role in the genesis of the human class I region. (C) 1994 Academic Press, Inc.